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United States Patent |
5,073,561
|
Coughenour
,   et al.
|
December 17, 1991
|
Methods of treating depression and psychoses
Abstract
Certain N-substituted 1-(1,2,3,6-tetrahydro-3-pyridinyl)oximes and
N-substituted 1-(1,2,3,6-tetrahydro-4-pyridinyl)oximes are useful as sigma
binding agents for the treatment of depression, psychoses and/or
inflammatory diseases.
Inventors:
|
Coughenour; Linda L. (Ann Arbor, MI);
Davis; Robert E. (Ann Arbor, MI);
Downs; David A. (Ann Arbor, MI);
Heffner; Thomas G. (Ann Arbor, MI);
Meltzer; Leonard T. (Ann Arbor, MI);
Moos; Walter H. (Ann Arbor, MI);
Moreland; David W. (Ann Arbor, MI);
Tecle; Haile (Ann Arbor, MI)
|
Assignee:
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Warner-Lambert Company (Morris Plains, NJ)
|
Appl. No.:
|
488591 |
Filed:
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March 5, 1990 |
Current U.S. Class: |
514/357 |
Intern'l Class: |
A61K 031/44 |
Field of Search: |
546/329
514/357
|
References Cited
U.S. Patent Documents
3004979 | Oct., 1961 | Druey et al. | 546/338.
|
Other References
Burger, "Medicinal Chemistry", 2nd Ed., 1960, Interscience Publishers,
Inc., N.Y., pp. 565-571, 579-581, 600-601.
|
Primary Examiner: Ramsuer; Robert W.
Attorney, Agent or Firm: Newtson; Ruth H.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This is a divisional application of U.S. Ser. No. 07/259,081 filed Oct. 18,
1988, now U.S. Pat. No. 4,929,734, which is a continuation-in-part of U.S.
Ser. No. 07/032,839 filed Mar. 31, 1987, now U.S. Pat. No. 4,798,841
issued Jan. 17, 1989.
Claims
We claim:
1. A method for treating depression in a mammal suffering therefrom which
comprises administering to such mammal an antidepressant effective amount
of a compound of the formula:
##STR12##
wherein R.sub.1 is selected from hydrogen;
straight or branched alkyl of from one to six carbon atoms substituted with
hydroxy or alkoxyl of from one to four carbon atoms;
straight or branched alkenyl of from two to six carbon atoms substituted
with hydroxy or alkoxyl of from one to four carbon atoms;
straight or branched alkynyl of from two to six carbon atoms optionally
substituted with hydroxy or alkoxyl of from one to four carbon atoms;
##STR13##
where A is a bond or is a hydrocarbon chain of from one to four carbon
atoms, optionally substituted with halogen, and when containing two or
more carbon atoms may contain one double bond and R.sub.3 is alkyl of from
one to six carbon atoms; or
##STR14##
where n is zero, two, three or four and X and Y are independently
selected from
hydrogen,
fluorine,
chlorine,
bromine,
hydroxy,
straight or branched alkyl of from one to three carbon atoms, or
alkoxyl of from one to four carbon atoms;
R.sub.2 is selected from hydrogen;
straight or branched alkynyl of from two to six carbon atoms optionally
substituted with hydroxy or alkoxyl of from one to four carbon atoms;
##STR15##
where n is zero to six and X and Y are independently selected from
hydrogen,
fluorine,
chlorine,
bromine,
hydroxy,
straight or branched alkyl of from one to three carbon atoms, or alkoxyl of
from one to four carbon atoms;
with the proviso that R.sub.1 and R.sub.2 may not both simultaneously be
hydrogen; or a pharmaceutically acceptable salt thereof.
2. A method for treating psychoses involving a sigma receptor in a mammal
suffering therefrom which comprises administering to such mammal an
antipsychotic effective amount of a compound of the formula:
##STR16##
wherein R.sub.1 is selected from hydrogen;
straight or branched alkyl of from one to six carbon atoms substituted with
hydroxy or alkoxyl of from one to four carbon atoms;
straight or branched alkenyl of from two to six carbon atoms substituted
with hydroxy or alkoxyl of from one to four carbon atoms;
straight or branched alkynyl of from two to six carbon atoms optionally
substituted with hydroxy or alkoxyl of from one to four carbon atoms;
##STR17##
where A is a bond or in a hydrocarbon chain of from one to four carbon
atoms, optionally substituted with halogen, and when containing two or
more carbon atoms may contain one double bond and R.sub.3 is alkyl of from
one to six carbon atoms; or
##STR18##
where n is zero, two, three or four and X and Y are independently
selected from
hydrogen,
fluorine,
chlorine,
bromine,
hydroxy,
straight or branched alkyl of from one to three carbon atoms, or
alkoxyl of from one to four carbon atoms;
R.sub.2 is selected from hydrogen;
straight or branched alkynyl of from two to six carbon atoms optionally
substituted with hydroxy or alkoxyl of from one to four carbon atoms;
##STR19##
where n is zero to six and X and Y are independently selected from
hydrogen,
fluorine,
chlorine,
bromine,
hydroxy,
straight or branched alkyl of from one to three carbon atoms, or alkoxyl of
from one to four carbon atoms;
with the proviso that R.sub.1 and R.sub.2 not both simultaneously by
hydrogen; or a pharmaceutically acceptable salt thereof.
Description
BACKGROUND OF THE INVENTION
The present invention relates to chemical compounds, pharmaceutical
compositions, and to a method of treatment employing the compounds and
compositions. More particularly, the present invention is concerned with
certain 1,2,5,6-tetrahydro-1-substituted 3- or 4-pyridine oximes, to
pharmaceutical compositions containing these compounds, and to a
pharmaceutical method of treatment.
Disorders of cognition are generally characterized by symptoms of
forgetfulness, confusion, memory loss, attentional deficits and/or, in
some cases, affective disturbances. These symptoms may arise as a result
of the general aging process and/or from organic brain disease,
cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging
process is well accepted. The same phenomenon has been observed and
documented in many lower mammals, including those routinely employed in
pharmacological testing programs for screening and predicting usefulness
for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process,
presenile and senile primary degenerative dementia are the most common
accepted causes of mental deterioration in the elderly. It has been
estimated that at least ten percent of persons over sixty years of age
will eventually suffer severe mental deterioration. A much larger number
will experience cognitive decline of sufficient severity to impede their
activities.
Many of the symptoms of cognitive disorders, especially impaired memory,
are associated with decreased acetylcholine synthesis and the impairment
of cholinoreceptive neurons. In the hippocampus and cerebral cortex of
patients suffering from primary degenerative dementia for example, the
level of the enzyme choline acetyltransferase (CAT) can be reduced by as
much as ninety percent. (See Davies et al., The Lancet, 1976 (Vol. 2):
1403; Perry et al., J. Neurol. Sci., 34: 247-265 (1977); and White et al.,
The Lancet, 1977 (Volume 1): 668-670).
Since CAT catalyzes the synthesis of acetylcholine from its precursors
choline and acetyl coenzyme A, the loss of CAT reflects the loss of
cholinergic, or acetylcholine-releasing, nerve endings in the hippocampus
and cerebral cortex. There is abundant evidence that cholinergic terminals
in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggests that drugs which restore acetylcholine
levels or which mimic the action of acetylcholine (i.e. are
cholinomimetic) are effective in correcting this deficit in
neurotransmitter chemical and provide treatment of the memory impairment
symptom of cerebral insufficiency. Considerable biochemical,
pharmacological, and electrophysiological evidence supports the hypothesis
that deficits in the cholinergic system underlie geriatric cognitive
dysfunction. (See C. Peterson and G. E. Gibson, Neurobiol. Aging, 4: 25-30
(1983)). Aged humans and non-human primates with decreased cognition show
improved memory when they are treated, for example, with
acetylcholinesterase inhibitors such as physostigmine. These agents
increase the available supply of synaptic acetylcholine by inhibiting its
hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive
deficits by increasing the release of acetylcholine from presynaptic nerve
terminals, thus increasing synaptic acetylcholine. (See H. P. Davis et
al., Exp. Aging Res., 9: 211-214 (1983)).
It has been known for some time that the natural alkaloid, muscarine, has
the ability to act relatively selectively at autonomic effector cells to
produce qualitatively the same effects as acetylcholine. Two related
alkaloids, pilocarpine and arecoline, have the same principal sites of
action as muscarine and acetylcholine and are thus classified as having
"muscarinic" action. Although these naturally occurring alkaloids are of
great value as pharmacological tools, present clinical use is largely
restricted to the use of pilocarpine as a miotic agent.
Arecoline (the methyl ester of
1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxylic acid) is the chief
alkaloid found in betel nuts (Areca catechu). Betel nuts have been chewed
by natives of the East Indies since early times as a euphoretic. The
present pharmaceutical utility of arecoline, however, has been limited to
its use as a veterinary anthelmintic agent.
Recently it has been demonstrated that arecoline is effective in
ameliorating some of the symptoms of cognitive disorders in patients
clinically diagnosed as having presenile primary degenerative dementia.
Significant improvement was observed in a test of picture recognition
after administration of arecoline to patients in a double blind study.
(See Christie et al., Brit. J. Psychiatry, 138: 46-50 (1981)).
Certain 3- or 4-ketoximes of 1-(lower alkyl)-1,2,5,6-tetrahydropyridines in
which the oxygen is unsubstituted are disclosed in U.S. Pat. No.
3,004,979, having utility as parasympathomimetic agents acting on
non-striated muscle.
Regarding analgesia, the literature indicates that acetylcholine and
muscarine agonists possess antinociceptive activity (see T. T. Chau et
al., J. Pharmacol. Exp. Ther., 222: 612-666 (1982),; W. L. Dewey et al.,
Life Sci., 17: 9-10 (1975); and N. W. Pedigo et al., Neurosci. Lett., 26:
85-90 (1981) and references cited therein).
The classification and nomenclature of phencyclidine and sigma receptor
sites has been reviewed (Trends Neurosci. 1987, 10: 444-446). See also
Clin. Neuropharmacol. 1988, 11: 105. The structural determinants of sigma
receptor affinity have been described (Mol. Pharmacol. 1987, 32: 772-784).
We have found that a new structural class of chemical compounds, e.g.
tetrahydropyridine oximes, have unexpectedly high affinity for the sigma
site.
Sigma receptor agonists may serve to modulate the actions of a variety of
transmitters (Eur. J. Pharmacol. 1988, 149: 399-400).
1,3-Disubstituted-guanidine sigma receptor ligands are useful in the
diagnosis and treatment of hallucination associated psychotic mental
illness (e.g., schizophrenia) and chronic mental depression (U.S. Pat. No.
4,709,094, Trends Neurosci. 1988, 11: 37-40.
Since haloperidol and many other antipsychotic drugs exhibit an affinity
for sigma receptors which is at least equal to its affinity for dopamine
receptors, these data raise the further possibility that sigma receptors
are involved in the motor side effects of antipsychotic drugs (Neurology
1988, 38: 961-965).
The sigma site plays a role in immune system functioning, for example, as
evidenced by steroid binding at sigma receptors and the link between
endocrine, nervous, and immune systems (Science 1988, 240: 219-221). See
also Eur. J. Pharmacol. 1988; 148: 467-470. Additionally, sigma ligands
prevent the proliferative response of T lymphocytes by lowering IL2
production (Biochem. Pharmacol. 1987, 36: 3929-3936). The aforementioned
articles suggest activity as antiinflammatories or immunosuppressants.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula 1:
##STR1##
wherein the
##STR2##
may be attached to the tetrahydropyridine moiety at either carbon atom
number 3 or 4 of the tetrahydropyridine ring system, and the attachment of
the OH group to the nitrogen atom is configured either syn- or anti- to
the tetrahydropyridine ring.
The substituent group R.sub.1 is hydrogen; straight or branched alkyl of
from one to six carbon atoms optionally substituted with hydroxy or
alkoxyl of from one to four carbon atoms; straight or branched alkenyl of
from one to six carbon atoms optionally substituted with hydroxy or
alkoxyl of from one to four carbon atoms; straight or branched alkynyl of
from one to six carbon atoms optionally substituted with hydroxy or
alkoxyl of from one to four carbon atoms; cycloalkyl of from three to
eight carbon atoms;
##STR3##
where A is a bond or is a hydrocarbon chain of from one to four carbon
atoms and when containing two or more carbon atoms may contain one double
bond and where R.sub.3 is alkyl of from one to six carbon atoms,
optionally substituted with halogen;
##STR4##
where n is zero to four and X and Y are independently selected from
hydrogen, fluorine, chlorine, bromine, hydroxy, straight or branched alkyl
of from one to three carbon atoms, or alkoxyl of from one to four carbon
atoms.
R.sub.2 is selected from hydrogen; straight or branched alkynyl of from one
to six carbon atoms optionally substituted with hydroxy or alkoxyl of from
one to four carbon atoms; cycloalkyl of from three to six carbon atoms; or
##STR5##
where n is zero to six and X and Y are independently selected from
hydrogen, fluorine, chlorine, bromine, hydroxy, straight or branched alkyl
of from one to three carbon atoms, or alkoxyl of from one to four carbon
atoms; with the proviso that R.sub.1 and R.sub.2 may not both
simultaneously be hydrogen; or a pharmaceutically acceptable acid addition
salt thereof.
In another aspect, the present invention provides a method of treating
depression in a mammal in need of such treatment comprising the
administration of an antidepressant effective amount of a compound of
formula 1 above in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of treating
psychoses, e.g. schizophrenia, in a mammal in need of such treatment
comprising the administration of an antipsychotic effective amount of a
compound of formula 1 above in combination with a pharmaceutically
acceptable carrier.
In another aspect, the present invention provides a method of treating
inflammation in a mammal in need of such treatment comprising the
administration of an antiinflammatory effective amount of a compound of
formula 1 above in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides pharmaceutical
compositions for treating depression comprising administering an
antidepressant effective amount of a compound of formula 1 above in
combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides pharmaceutical
compositions for treating psychoses, e.g. schizophrenia, comprising
administering an antipsychotic effective amount of a compound of formula 1
above in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides pharmaceutical
compositions for treating inflammation comprising administering an
antiinflammatory effective amount of a compound of formula 1 above in
combination with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
The compounds of the present invention comprise a class of
1,2,5,6-tetrahydro-1-substituted 3- or 4-pyridine oximes and their
pharmaceutically acceptable salts which are centrally acting muscarinic
agents and which are thus useful as analgesic agents, sleep aids, or
therapeutic agents for treating cholinergic deficit states such as senile
dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia,
hyperkinesia, mania or similar conditions of cerebral insufficiency
characterized by decreased cerebral acetylcholine production or release.
The compounds of the present invention are also active at the sigma site
and as sigma agents are useful for treating depression, psychoses, e.g.
schizophrenia, and inflammatory diseases
The substituent group R.sub.1 in structural formula 1 above is selected
from hydrogen; straight or branched alkyl of from one to six carbon atoms
optionally substituted with hydroxy or alkoxyl of from one to four carbon
atoms; straight or branched alkenyl of from one to six carbon atoms
optionally substituted with hydroxy or alkoxyl of from one to four carbon
atoms; straight or branched alkynyl of from one to six carbon atoms
optionally substituted with hydroxy or alkoxyl of from one to four carbon
atoms; cycloalkyl of from three to eight carbon atoms
##STR6##
where A is a bond or a hydrocarbon chain of from zero to four carbon atoms
and when containing two or more carbon atoms may contain one double bond
and R3 is alkyl of from one to six carbon atoms, optionally substituted
with halogen; or
##STR7##
where n is zero to four X and Y are independently selected from hydrogen,
fluorine, chlorine, bromine, hydroxy, straight or branched alkyl of from
one to three carbon atoms, or alkoxyl of from one to four carbon atoms.
The term "alkyl of from one to six carbon atoms" denotes a substituent
group derived from a saturated hydrocarbon by removal of a single hydrogen
atom. The term includes methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, and the various isomeric forms of pentyl
and hexyl. Likewise, the terms "alkenyl of from one to six carbon atoms"
and "alkynyl of from one to six carbon atoms" denote substituent groups
derived, respectively, from alkene or alkyne hydrocarbons by the removal
of a single hydrogen atom. These terms include ethenyl, ethynyl, propenyl,
propynyl, and similar branched and unbranched unsaturated hydrocarbon
groups of up to six carbon atoms.
The term "cycloalkyl of from three to eight carbon atoms" denotes saturated
carbocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, as well as alkyl substituted carbocyclic rings containing up
to eight carbon atoms such as methyl-, dimethyl-, and ethylcyclohexyl.
The term "alkoxyl" denotes a substitent group derived by removal of the
hydrogen from the oxygen atom of a saturated alcohol and attached to the
parent molecular moiety through the oxygen atom. Such groups include
methoxyl, ethoxyl, 1- and 2-propoxyl, and similar branched and unbranched
alkoxyl groups of up to four carbon atoms.
In compounds of the present invention, the substituent group R.sub.2 is
selected from hydrogen; straight or branched alkynyl of from one to six
carbon atoms optionally substituted with hydroxy or alkoxyl of from one to
four carbon atoms; cycloalkyl of from three to six carbon atoms; or
##STR8##
where n is zero to six and X and Y are independently selected from
hydrogen, fluorine, chlorine, bromine, hydroxy, straight or branched alkyl
of from one to three carbon atoms, or alkoxyl of from one to four carbon
atoms.
Preferred compounds for use in the pharmaceutical methods of the present
invention are those in which R.sub.1 is alkyl and R.sub.2 is
##STR9##
where n is zero to four.
The compounds employed in the method of this invention may exist in either
of two isomeric forms in which the hydrogen atom of the oxime group may be
either syn- or anti- with respect to the tetrahydropyridine ring. The
present invention includes both forms of the compounds as well as mixtures
of the syn- and anti- forms. Moreover, in those compounds in which there
is a double bond in a carbon chain, both the Z (i.e. cis-) and E (i.e.
trans) forms are included in the present invention. The terms syn- and
anti- as they apply to the compounds of the present invention are
illustrated by formulas 1a and 1b:
##STR10##
Examples of compounds contemplated as falling within the scope of the
present invention include, but are not limited to the following:
3-Phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone oxime.
1-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)-3-butyn-1-one oxime.
Phenyl(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)methanone oxime.
3-Phenyl-1-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-1-propanone oxime.
1-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)-4-hexyn-1-one oxime.
Compounds of the present invention are prepared by the general synthetic
method detailed in Reaction Sequence 1, following.
Referring to the Reaction Sequence, the starting 3- or 4-ketopyridines, 5,
are prepared by one of three alternative methods. In the first method, the
known 3- or 4-pyridinecarbonitriles, 2, are reacted in the conventional
manner with the desired alkyl lithium compound or the appropriate Grignard
reagent in an aprotic solvent such as diethyl ether, tetrahydrofuran,
dioxane or the like, followed by hydrolysis in dilute aqueous acid. In the
second method, the known 3- or 4-pyridinecarbonyl chlorides, 3, are
reacted in the usual manner with the desired alkynyl or aralkyl
organometallic compound in the presence of a copper(I) halide. Preferred
organometallic compounds are Grignard reagents or organolithium compounds.
##STR11##
In the third alternative method, the known 3- or
4-pyridinecarboxaldehydes, 4, from which the aldoximes may be prepared
directly, are reacted in the usual manner with the desired Grignard
reagent followed by oxidation of the carbinol thus produced by manganese
dioxide or by the method of D. Swern, et al., J. Org. Chem., 43: 2480-2482
(1978).
The 3- or 4-ketopyridines, 5 thus produced, are reacted with a diol such as
ethanediol in the presence of acid to produce the 3- or 4-pyridineketals,
6. The ketals, 6, are converted by the action of the desired alkynyl, or
aralkyl halide (preferably the iodide) to the corresponding
N-substitutedpyridinium ketals, 7. The N-substitutedpyridinium ketals, 7,
are subsequently reduced by the action of an alkali metal hydride, such as
sodium borohydride, to produce the N-substituted 3- or
4-ethylenedioxyketal-1,2,5,6-tetrahydropyridines, 8.
The 3- or 4-ethylenedioxyketal-1,2,5,6-tetrahydropyridines, 8, are next
converted to the corresponding N-substituted 3- or
4-keto-1,2,5,6-tetrahydropyridines, 9, by the action of aqueous acid. The
3- or 4-keto-1,2,5,6-tetrahydropyridines, 9, are then reacted with
hydroxylamine hydrochloride in, for example, methanol under reflux for a
period sufficient to effect the formation of the corresponding oximes, 10.
Alternatively, the unsubstituted oximes, 13, are converted to the
corresponding N-substituted pyridinium iodides by reaction with the
desired iodide. These pyridinium salts are reduced by the action of sodium
borohydride, generally in a mixed water/alcohol medium at ambient
temperature, to produce the N-substituted 3- or
4-oximino-1,2,5,6-tetrahydropyridine compounds of the present invention.
By virtue of the basic nitrogen atom in the tetrahydropyridine ring, the
compounds of the present invention form pharmaceutically acceptable acid
addition salts with organic and inorganic acids. Examples of suitable
acids for the formation of pharmaceutically acceptable salts are
hydrochloric, sulfuric, phosphoric, acetic, benzoic, citric, malonic,
salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic,
ascorbic, maleic, aspartic, benzenesulfonic, methane- and ethanesulfonic,
hydroxymethane and hydroxyethanesulfonic, and the like. (See for example,
"Pharmaceutical Salts," J. Pharm. Sci. 66 (1): 1-19 (1977)).
In a similar manner, the N-lower-alkyl and lower-dialkyl
tetrahydropyridinium salts may be used in the method of this invention as,
for example the N-methyl-, N,N-dimethyl- and
N-ethyl-1,2,5,6-tetrahydropyridinium halides.
The acid addition salts are prepared by contacting the free base form of
the compounds of this invention with a sufficient amount of the desired
acid to produce the salt in the conventional manner. The free base forms
may be regenerated, if desired, by treating the salt form with a base. For
example, dilute aqueous solutions of such bases as sodium hydroxide,
potassium carbonate, ammonia, and sodium bicarbonate may be utilized for
this purpose.
The free acid or base forms of the compounds of this invention differ
somewhat from their respective salt forms in such physical properties as
melting point and solubility in polar solvents, but the salts are
otherwise equivalent to their respective free acid or base forms for the
purposes of the invention.
The compounds of the present invention are sigma receptor agonists and as
sigma agents are thus useful as antidepressants for the treatment of
depression in mammals including man, as antipsychotics for treating
psychoses, e.g. schizophrenia, and as agents for treating inflammatory
diseases.
The biological activity of compounds of the present invention was evaluated
using a number of tests. The activity of compounds of this invention as
sigma site agonists was measured by the method described in Mol.
Pharmacol. 1987, 32: 772-784. IC.sub.50 values for the sigma site of 0.7
nM and 5 nM were found for
3-phenyl-1-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)propanone oxime and
3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)propanone oxime.
3-Phenyl-1-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)propanone oxime was
also evaluated in a test that measures spontaneous exploratory activity
and motor coordination (MAST). The experimental aspects of this test are
described in Pharmacol. Biochem. Behav. 1977; 6: 351-353 and Life Sci.
1978; 22: 1067-1076. Administered subcutaneously, the compound produced
significant (p<0.05) inhibition of spontaneous activity in rats; the
ED.sub.50 was 33.2 mg/kg. Essentially no discoordination was noted in mice
or rats.
As an example of the compounds of the present invention,
3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)propanone oxime was
subjected to the self-stimulation test. This test as applied for
antidepressant discovery involves the ability of antidepressant drugs to
potentiate the stimulatory effect of methamphetamine on intracranial
self-stimulation responding in rats.
Rats with stimulating electrodes implanted in the lateral hypothalamus were
trained to depress a lever in order to deliver rewarding electric current
to their brains, as described by Poschel and Ninteman in Life Sciences,
vol. 3, pp. 903-910, 1964. Groups of four rats performed self-stimulation
(SS) behavior for one hour and were then removed from the test apparatus
and given an oral injection of water, the subject compound (10 or 20
mg/kg) or the antidepressant reference agent, imipramine (10 mg/kg). Rats
were then returned to the apparatus and allowed to perform SS for another
1.5 hours at which time they were again removed from the box and were
given an intraperitoneal injection of methamphetamine (0.25 mg/kg). Rats
were then returned to the apparatus and allowed to perform SS for 5.5
hours. The number of lever presses made per 30 minute interval were
recorded. Drug effects were compared during the first hour after
methamphetamine administration.
Antidepressant drugs, such as imipramine, increase the number of lever
presses made after methamphetamine treatment. The data in Table 1
demonstrate that
3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)propanone oxime showed
effects similar to those of imipramine in the SS test. That is, rats given
the subject compound or imipramine prior to methamphetamine showed an
increased number of SS lever presses as compared to control rats given
water prior to methamphetamine.
TABLE 1
______________________________________
Effects of 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-
pyridinyl)propanone oxime (compound) and the antidepressant
drug imipramine on the increase in self-stimulation (SS)
responding produced by methamphetamine in rats.
SS Responses
Treatment (Mean .+-. S.E.M.)
______________________________________
Vehicle + Methamphetamine
2317 .+-. 473
Compound, 10 mg/kg + Methamphetamine
4409 .+-. 630*
Compound, 20 mg/kg + Methamphetamine
5149 .+-. 467*
Imipramine, 10 mg/kg + Methamphetamine
4199 .+-. 259*
______________________________________
*Significantly different than Vehicletreated group (p < .05)
Finally, 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)propanone
oxime, a representative compound of the present invention, was subjected
to the Porsolt behavioral despair test which involves the ability of
antidepressant drugs to reduce the duration of time that rats remain
immobile when they are forced to swim in a narrow water-filled cylinder.
In this test, rats are placed in a narrow cylinder filled with water for 15
minutes on the day prior to the drug test. Typically, the rats swim for a
time in an apparent attempt to escape but eventually cease attempts to
escape, remain immobile and float with their snouts above the surface.
Rats are then removed from the cylinders, dried under a heat lamp and
returned to their home cages. After the swim on day 1 and 30 minutes
before testing on the next day, drugs or the vehicle solution are
administered intraperitoneally and the rats are again placed in the
water-filled cylinders. The duration of immobility is measured during a 5
minute test. Antidepressant drugs are active in the behavioral despair
test at doses that do not simulate locomotor activity as reported by
Porsolt et al., European Journal of Pharmacology, vol. 47, pp. 379-391,
1978.
Groups of 10 rats were treated with saline, the subject compound (30 mg/kg)
or imipramine (30 mg/kg) on day 1 and one hour prior the test on day 2.
In order to ensure that the effect of the subject compound in the
behavioral despair test was not simply due to a general stimulant effect
of the compound, the effects of the subject compound (30 mg/kg) and
imipramine (30 mg/kg) on locomotor activity was determined in separate
groups of rats. For this test, rats were placed in darkened cylindrical
chambers and locomotor activity was recorded for 30 minutes by means of
photoelectric cells. The number of interruptions of the photocell beam
indicated the amount of locomotion.
Whereas control rats rapidly become immobile and remain so for about more
than half of the test, rats treated with antidepressant drugs continue to
swim about the cylinder and thus display less immobility than controls.
The data in Table 2 demonstrate that the subject compound, like
imipramine, reduced the duration of immobility in the behavioral despair
test. Table 2 also shows that neither the subject compound nor imipramine
increased spontaneous locomotion in rats when dosed as in the behavioral
despair procedure. Thus, the subject compound displayed a profile similar
to that seen with the antidepressant imipramine in the Porsolt behavioral
despair test.
TABLE 2
______________________________________
Effect of 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-
pyridinyl)propanone oxime (compound) and the antidepressant
drug imipramine in the Porsolt behavioral despair and
locomotor activity tests in rats.
Behavioral Locomotor
Despair Test Activity Test
Treatment (Seconds Immobile)
(Counts)
______________________________________
Vehicle 192 .+-. 9 165 .+-. 14
Imipramine - 30 mg/kg
82 .+-. 14* 93 .+-. 17*
Compound - 30 mg/kg
121 .+-. 14* 139 .+-. 26
______________________________________
*Significantly different than Vehicle treatment, p < .05
In therapeutic use as agents for treating depression, psychoses or
inflammation, the compounds utilized in the pharmaceutical method of this
invention are administered to the patient at dosage levels of from 0.7 to
7000 mg per day. For a normal human adult of approximately 70 kg of body
weight, this translates into a dosage of from 0.01 to 100 mg/kg of body
weight per day. The specific dosages employed, however, may be varied
depending upon the requirements of the patient, the severity of the
condition being treated, and the activity of the compound being employed.
The determination of optimum dosages for a particular situation is within
the skill of the art.
For preparing pharmaceutical compositions from the compounds of this
invention, inert, pharmaceutically acceptable carriers can be either solid
or liquid. Solid form preparations include powders, tablets, dispersable
granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances which may also act as
diluents, flavoring agents, solubilizers, lubricants, suspending agents,
binders, or tablet disintegrating agents; it can also be an encapsulating
material.
In powders, the carrier is a finely divided solid which is in a mixture
with the finely divided active component. In tablets, the active compound
is mixed with the carrier having the necessary binding properties in
suitable proportions and compacted in the shape and size desired.
For preparing suppositories, a low-melting wax such as a mixture of fatty
acid glycerides and cocoa butter is first melted, and the active
ingredient is dispersed therein by, for example, stirring. The molten
homogeneous mixture is then poured into convenient sized molds and allowed
to cool and solidify.
Powders and tablets preferably contain between about 5 to about 70% by
weight of the active ingredient. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin,
starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
The term "preparation" is intended to include the formulation of the active
compound with encapsulating material as a carrier providing a capsule in
which the active component (with or without other carriers) is surrounded
by a carrier, which is thus in association with it. In a similar manner,
cachets are also included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms
suitable for oral administration.
Liquid form preparations include solutions suitable for oral or parenteral
administration, or suspensions, and emulsions suitable for oral
administration. Sterile water solutions of the active component or sterile
solutions of the active component in solvents comprising water, ethanol,
or propylene glycol may be mentioned as examples of liquid preparations
suitable for parenteral administration.
Sterile solutions may be prepared by dissolving the active component in the
desired solvent system, and then passing the resulting solution through a
membrane filter to sterilize it or, alternatively, by dissolving the
sterile compound in a previously sterilized solvent under sterile
conditions.
Aqueous solutions for oral administration can be prepared by dissolving the
active compound in water and adding suitable flavorants, coloring agents,
stabilizers, and thickening agents as desired. Aqueous suspensions for
oral use can be made by dispersing the finely divided active component in
water together with a viscous material such as natural or synthetic gums,
resins, methyl cellulose, sodium carboxymethyl cellulose, and other
suspending agents known to the pharmaceutical formulation art.
Preferably, the pharmaceutical preparation is in unit dosage form. In such
form, the preparation is divided into unit doses containing appropriate
quantities of the active component. The unit dosage form can be a packaged
preparation, the package containing discrete quantities of the
preparation, for example, packeted tablets, capsules, and powders in vials
or ampoules. The unit dosage form can also be a capsule, cachet, or tablet
itself, or it can be the appropriate number of any of these packaged
forms.
The following preparative examples are provided to enable one skilled in
the art to practice the invention. They are illustrative of the present
invention and are not to be read as limiting the scope of the invention as
it is defined by the appended claims.
EXAMPLES OF GENERAL SYNTHETIC METHODS AND PREPARATION OF STARTING MATERIALS
Example 1
Representative Example of the Conversion of a Pyridine Carboxaldehyde to a
Ketopyridine--Preparation of 1-(3-Pyridinyl)propanone
3-Pyridinecarboxaldehyde (10.71 g, 100 mmol) was dissolved in 200 ml of
tetrahydrofuran under a nitrogen atmosphere and cooled to -30.degree. C.
Ethylmagnesium bromide (100 mmol, 2.0 molar in tetrahydrofuran) was slowly
added, after which the mixture was stirred at -30.degree. C. for one hour.
Saturated ammonium chloride solution was added and the mixture was allowed
to warm to room temperature. Diethyl ether (200 ml) was added and the
organic layer was separated, dried over anhydrous magnesium sulfate, and
evaporated to yield the intermediate carbinol as a yellow oil. This
material was taken up in 500 ml of toluene, and 26.1 g (300 mmol) of
manganese dioxide was added. The resulting mixture was heated under reflux
for two hours under a nitrogen atmosphere in a flask fitted with a Dean
Strak trap to collect water which was azeotropically removed.
The reaction mixture was cooled to room temperature and diluted by the
addition of diethyl ether. The reaction mixture is filtered and the
solvents were removed from the filtrate under vacuum and the crude product
purified by chromatography on a silica gel column, eluting with 1:1
hexane/ethyl acetate to produce 7.09 g of 1-(3-pyridinyl)-1-propanone.
Example 2
Representative Example of the Conversion of a Pyridinecarbonyl Chloride to
a Ketopyridine--Preparation of 1-(3-Pyridinyl)pentanone
Copper(I) iodide (3.8 g, 2.0 mmol) was suspended in 30 ml of dry
tetrahydrofuran which was then cooled to -40.degree. C. n-Butyl lithium
solution (16 ml, 2.5 molar in tetrahydrofuran) was added and the mixture
further cooled to -78.degree. C. and stirred for one hour.
3-Pyridinecarbonyl chloride hydrochloride (1.78 g, 10 mmol) was quickly
added, and the resulting mixture was allowed to slowly warm to room
temperature. The reaction was quenched by the addition of 2 ml of
methanol, and the mixture partitioned between diethyl ether and 1:1
saturated aqueous ammonium chloride/aqueous ammonia.
This mixture was stirred until the aqueous layer became dark blue (copper
ammonia complex), after which the layers were separated. The organic layer
was washed successively with portions of 10% aqeuous Na.sub.2 S.sub.2
O.sub.3, water, and brine, and then dried over anhydrous magnesium
sulfate. The solvent was removed under vacuum and the crude product
chromatographed on silica gel, eluting with 70% hexane in ethyl acetate,
to yield 0.80 g of 1-(3-pyridinyl)-1-pentanone.
Example 3
Representative Example of the Preparation of a Ketopyridine by the Swern
Oxidation of an Intermediate Carbinol Prepared via Grignard
Reaction--Preparation of 2-Methyl-1-(3-pyridinyl)-1-propanone
Oxalyl chloride was distilled under a nitrogen atmosphere immediately prior
to use; 10.93 g (86.13 mmol) was dissolved in 200 ml of dichloromethane.
This mixture was cooled, under a nitrogen atmosphere, to -50.degree. C.
and 13.45 g (12.22 ml, 172.3 mmol) of dry dimethylsulfoxide in 50 ml of
dichloromethane were slowly added. The resulting mixture was stirred at
-50.degree. C. for ten minutes. .alpha.-(1-Methylethyl)-3-pyridinemethanol
(11.84 g, 78.3 mmol, previously prepared by reaction of
3-pyridinecarboxaldehyde with isopropylmagnesium bromide) in 50 ml of
dichloromethane was added. This mixture was stirred at -50.degree. C. for
one hour, after which time 39.6 g (54.57 ml, 391.5 mmol) of triethylamine
were added. This mixture was allowed to slowly warm to room temperature.
Water (300 ml) was added to the mixture, and the layers were separated. The
water layer was extracted twice with dichloromethane, and the organic
solutions were combined, washed with successive portions of 10% aqueous
sodium carbonate solution, and brine, and then dried over anhydrous
magnesium sulfate. The solvents were removed under vacuum, and the crude
product was chromatographed over silica gel, eluting with 15% ethyl
acetate in chloroform to yield 10.3 g of
2-methyl-1-(3-pyridinyl)-1-propanone.
Example 4
Representative Example of the Conversion of a Ketopyridine to a
Keto-1,2,5,6-tetrahydropyridine--Preparation of
1-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)-1-pentanone
1-(3-Pyridinyl)-1-pentanone (4.53 g, 27.75 mmol, prepared as described in
Example 2 above), 1,2-ethanediol (2.58 g, 2.32 ml, 41.63 mmol), and
p-toluenesulfonic acid (6.3 g, 33.3 mmol) were dissolved in 50 ml of
toluene at room temperature. This mixture was heated under reflux for
twenty hours in a flask fitted with a Dean Stark trap to collect
azeotropically distilled water.
After this time, the mixture was cooled and poured into 10% aqueous sodium
carbonate solution and the resulting mixture diluted with diethyl ether.
The organic layer was separated, dried over anhydrous magnesium sulfate,
and evaportaed to yield the crude ethylene ketal as an orange oil. The
crude product was purified by chromatography over silica gel, eluting with
70% hexane in ethyl acetate to produce 4.22 g of the pure material.
The ethylene ketal was mixed with 10 ml of methyl iodide and stirred at
room temperature for three days. The excess methyl iodide was removed
under vacuum, and the residue triturated with diethyl ether to obtain 6.78
g of the N-methylpyridinium ethylene ketal iodide.
The N-methylpyridinium ethylene ketal iodide was dissolved in 60 ml of
absolute ethanol under nitrogen, and 0.81 g of sodium borohydride were
slowly added, keeping the temperature of the reaction mixture under
25.degree. C. This was followed by addition of another 1.32 g of sodium
borohydride. This mixture was stirred at room temperature for 30 minutes,
after which time the mixture was heated under reflux for thirty minutes.
The reaction mixture was cooled to room temperature and 21 ml of 6M aqueous
hydrochloric acid were slowly added. After addition of the acid was
complete, the resulting mixture was heated under reflux for one hour and
then cooled to room temperature. The alcohol was removed under vacuum
leaving a yellowish slurry.
Fifty ml of water were added, followed by the slow addition of 20 g of
potassium carbonate. The resulting mixture was extracted twice with
diethyl ether and the extract was dried over anhydrous magnesium sulfate.
The ether was evaporated and the residue was purified by column
chromatography over silica gel, eluting with 5% methanol in diethyl ether,
to yield 2 g of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-pentanone as
a yellow oil. This material was reacted with oxalic acid to yield 1.3 g of
the ethanedioate salt, mp 171.degree.-172.degree. C.
Example 5
Representative Example of the Preparation of a 1,2,5,6-Tetrahydropyridine
Oxime by the Oximination of a Keto-1,2,5,6-tetrahydropyridine--Preparation
of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-pentanone Oxime
To a solution of 1.09 g (6.01 mmol) of
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-pentanone (prepared as
described in Example 4 above) in 6 ml of methanol were added 0.42 g (6.1
mmol) of hydroxylamine hydrochloride. The resulting mixture was heated
under reflux for 12 hours, cooled, and stirred at room temperature for
three days. The solvent was removed under vacuum and chloroform and dilute
aqueous ammonium hydroxide solution were added. The chloroform layer was
separated, washed with water until it tested neutral, and dried over
anhydrous magnesium sulfate. The chloroform was removed under vacuum and
the residual dark oil was taken up in diethyl ether. This solution was
filtered through silica gel and the ether removed under vacuum. The
residue was reacted with oxalic acid to produce
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-pentanone oxime,
ethanedioate salt, mp 91.degree.-95.degree. C.
Example 6
Representative Example of the Conversion of a Ketopyridine to a
1-Methyl-ketoxime-1,2,5,6-tetrahydropyridine via the Ketopyridine
Oxime--Preparation of 1-(1,2,5,6-tetrahydro-1-methylpyridinyl)ethanone
Oxime
Step 1--Preparation of 1-(3-pyridinyl)ethanone oxime
A mixture of 50 g (0.41 mol) of 1-(3-pyridinyl)ethanone and 29 g (0.42 mol)
of hydroxylamine hydrochloride in 250 ml of methanol was heated under
reflux for five hours. Upon cooling to room temperature, a white solid
separated from the reaction mixture. This material was collected by
filtration and the filtrate was concentrated to yield additional white
solid. The combined solids were dissolved in water and the solution was
made weakly basic by the addition of sodium bicarbonate solution while
cooling. The white precipitate which formed was separated by filtration to
yield 55.4 g of 1-(3-pyridinyl)ethanone oxime, mp 115.degree.-117.degree.
C.
Step 2--Preparation of 1-(3-pyridinyl)ethanone oxime methiodide
1-(3-pyridinyl)ethanone oxime (8.8 g, 0.073 mol) was dissolved in 500 ml of
acetonitrile and 10 ml (0.16 mol) of methyl iodide were added. The
resulting mixture was heated under reflux for four hours and then cooled
to room temperature. The white precipitate was collected by filtration to
yield 16.45 g of 1-(3-pyridinyl)ethanone oxime methiodide, mp
219.degree.-220.degree. C.
Step 3--Preparation of 1-(1,2,5,6-tetrahydro-1-methylpyridinyl)ethanone
oxime
To a suspension of 5 g of sodium borohydride in 100 ml of 50:50
water/methanol was added, in a dropwise manner, 50 ml of a solution of
19.5 g (0.07 mol) of 1-(3-pyridinyl)ethanone oxime methiodide dissolved in
50 ml of 50:50 water/methanol while maintaining the temperature between
-5.degree. C. and 0.degree. C.
The mixture was then allowed to warm to room temperature and was diluted
with 200 ml of water. This mixture was stirred for a few minutes and the
light yellow precipitate which formed was collected by filtration to yield
7.83 g of 1-(1,2,5,6-tetrahydro-1-methylpyridinyl)ethanone oxime, mp
154.degree.-157.degree. C.
PREPARATIVE EXAMPLES FOR COMPOUNDS OF THE PRESENT INVENTION
Example 7
Preparation of
3-Phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)propanone Oxime
Step 1--Preparation of 3-phenyl-1-(3-pyridinyl)-1-propanone
Employing the general method of Example 1 above, 21.42 g (0.225 mol) of
pyridine-3-carboxaldehyde and 27.3 ml (0.200 mol) of 2-phenylethyl bromide
were converted by Grignard reaction to 40 g (94%) of
(2-phenyl-3-pyridinyl)methanol and then oxidized by the action of
manganese dioxide to yield a mixture of
3-phenyl-1-(3-pyridinyl)-1-propanone and
3-phenyl-1-(3-pyridinyl)-2-propen-1-one. This mixture was reduced by
hydrogen over Raney nickel to produce 17.1 g of
3-phenyl-1-(3-pyridinyl)-1-propanone.
Step 2--Preparation of
3-phenyl-1-(1,2,5,6-tetrahydromethyl-3-pyridinyl)-1-propanone oxime
Employing the general methods of Examples 4 and 6 above, 10 g (47.3 mmol)
of 3-phenyl-1-(3-pyridinyl)-1-propanone were first converted by the action
of methyl iodide to the N-methylpyridinium iodide and then reduced by the
action of sodium borohydride to produce
3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone which was
isolated as the hydrochloride salt (5.2 g, 58%), mp
195.degree.-197.degree. C.
Example 8
Preparation of 1-(1,2,5,6-Tetrahydro-1-methyl-3-pyridinyl)-3-butyne-1-one
Oxime
Step 1--Preparation of 4-trimethylsilyl-3-butyne-1-ol
A solution of 2 mol of ethyl magnesium bromide (2.0 molar solution in
tetrahydrofuran) is cooled in an ice bath and a solution of 50.5 g of
3-butyn-1-ol (0.72 mol) in 50 ml of tetrahydrofuran is slowly added. After
addition is complete, the mixture was allowed to warm to room temperature
and was stirred overnight. The mixture was then cooled in an ice bath and
254 ml (2 mol) of chlorotrimethylsilane was slowly added. This mixture was
heated under reflux for two hours and then cooled to 20.degree. C. and 800
ml of 1.4M aqueous sulfuric acid were added. The mixture was extracted
with diethyl ether and the ether solution was dried and concentrated under
vacuum. The residue was distilled to yield 72.8 g of
4-trimethylsilyl-3-butyne-1-ol, bp 43.degree.-48.degree. C. at 1 mm Hg.
Step 2--Preparation of 4-Bromo-1-trimethylsilyl-1-butyne
4-Trimethylsilyl-3-butyne-1-ol (14.2 g, 0.1 mol) and 0.2 ml of pyridine
were dissolved in 50 ml of diethyl ether under a nitrogen atmosphere.
Phosphorus tribromide (3.8 ml, 0.04 mol) was slowly added and the mixture
was heated under reflux for two hours. Isolation of the product by
conventional means yielded 9.6 g of 4-bromo-1-trimethylsilyl-1-butyne as a
clear liquid, bp 35.degree.-38.degree. C. at 1 mm Hg.
Step 3--Preparation of (4-trimethylsilylbutyn-3-yl-3-pyridinyl)methanol
Employing the general method of Example 1 above, 10.7 g (0.1 mol) of
pyridine-3-carboxaldehyde and 20.5 g (0.1 mol) of
4-bromo-1-trimethylsilyl-1-butyne were converted by Grignard reaction to
5.9 g (25%) of (4-trimethylsilylbutyn-3-yl-3-pyridinyl)methanol which was
employed without further purification.
Step 4--Preparation of (3-butynyl-3-pyridinyl)methanol
Four ml of a 1.0M solution of tetrabutylammonium fluoride in
tetrahydrofuran was added to 0.75 g (3.21 mmol) of
(4-trimethylsilylbutyn-3-yl-3-pyridinyl)methanol in 3 ml of
tetrahydrofuran and the resulting mixture was stirred at room temperature
for 30 minutes. Isolation of the product yielded 0.12 g of
(3-butynyl-3-pyridinyl)methanol as a brown oil.
Step 5--Preparation of 1-(3-pyridinyl)-3-butyn-1-one
Employing the Swern oxidation method of Example 3 above, 4.8 g (29.9 mmol)
of (3-butynyl-3-pyridinyl)methanol was oxidized to 2.95 g (62%) of 1-(3-
pyridinyl)-3-butyn-1-one.
Step 6--Preparation of 1-(3-pyridinyl)-3-butyne-1-one oxime
Employing the general method of Example 5 above, 2.95 g (18.5 mmol) of
1-(3-pyridinyl)-3-butyne-1-one was converted to 2.1 g (66%) of the
corresponding oxime by reaction with hydroxylamine hydrochloride.
Step 7--Preparation of
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-3-butyne-1-one oxime
Employing the general method of Example 6 above, 2.12 g (12.2 mmol) of
1-(3-pyridinyl)-3-butyne-1-one oxime were converted to the corresponding
1-methyl pyridinium iodide and subsequently reduced by the action of
sodium borohydride to produce 1.2 g of
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-3-butyne-1-one oxime which was
isolated as the ethanedioate salt, mp 55.degree.-57.degree. C.
Example 9
Preparation of
4-Methoxy-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-butanone Oxime
Step 1--Preparation of 4-Chloro-1-methoxybutane
4-Chloropropanol (47.3 g, 0.5 mol) and 62.2 ml (1 mol) of methyl iodide
were dissolved in 300 ml of tetrahydrofuran and the resulting solution was
cooled in an ice bath. A suspension of 40 g (1 mol) of sodium hydride in
oil was slowly added. When addition was complete, the reaction mixture was
allowed to warm to room temperature and was stirred overnight.
The mixture was again cooled in an ice bath and 150 ml of water were added
to quench the reaction. The organic layer was separated, dried over
anhydrous magnesium sulfate, and the solvent evaporated under vacuum. The
residue was distilled to yield 27.6 g of 4-chloro-1-methoxybutane, bp
111.degree.-113.degree. C.
Step 2--Preparation of 3-(Methoxypropyl)-3-pyridinylmethanol
Following the general method of Example 1, 21.7 g (0.2 mol) of
4-chloro-1-methoxypropane and 21.4 g (0.2 mol) of
pyridine-3-carboxaldehyde were converted to 18.87 g (52%) of
(4-methoxypropyl-3-pyridinyl)methanol.
Step 3--Preparation of 4-methoxy-1-(1-methyl-3-pyridinyl)butanone
Employing the Swern oxidation method of Example 3, 25.67 g (0.142 mol) of
(4-methoxypropyl-3-pyridinyl)methanol were converted to 17.6 g (69%) of
4-methoxy-1-(1-methyl-3-pyridinyl)butanone as a yellow oil which was used
without further purification.
Step 4--Preparation of 4-methoxy-1-(1-methyl-3-pyridinyl)butanone oxime
Employing the general method of Example 5, 8.96 g (50 mmol) of
1-(1-methyl-3-pyridinyl)butanone was converted to the corresponding oxime
by reaction with 3.82 g (55 mmol) of hydroxylamine hydrochloride. The
product (9.5 g, 98%) was isolated as a thick reddish oil which was used
without further purification.
Step 5--Preparation of
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-4-methoxybutanone oxime
Employing the general method of Example 6 above, 9.5 g (49 mmol) of
4-methoxy-1-(1-methyl-3-pyridinyl)butanone oxime were first converted to
16.5 g of the N-methyl pyridinium iodide salt and then reduced to
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-4-methoxybutanone oxime by the
action of sodium borohydride.
The title compound was isolated as the ethanedioate salt, mp
114.degree.-116.degree. C.
Employing the methods detailed above, the following additional compounds
were prepared:
TABLE 4
______________________________________
Example Compound Name M.P.
______________________________________
10 1,2,5,6-Tetrahydro-1-methyl-
249-251.degree. C.
3-pyridinecarboxaldehyde oxime
(Isolated as the monohydrochloride)
11 2-Methyl-1-(1,2,5,6-tetrahydro-
98-102.degree. C.
1-methyl-3-pyridinyl)-1-propanone
oxime
(Isolated as the ethanedioate)
12 1-(1,2,5,6-Tetrahydro-1-methyl-
70-75.degree. C.
3-pyridinyl)-4-penten-1-one oxime
(Isolated as the monohydrochloride)
13 1-[1,2,5,6-Tetrahydro-1-(1-methyl-
110-111.degree. C.
ethyl)-3-pyridinyl]ethanone oxime
14 1-(1-Ethyl-1,2,5,6-tetrahydro-
>250.degree. C.
3-pyridinyl)ethanone oxime
(Isolated as the monohydrochloride)
15 1-[1,2,5,6-Tetrahydro-1-(2-
102-104.degree. C.
propenyl)-3-pyridinyl]ethanone
oxime
16 Phenyl(1,2,5,6-tetrahydro-
225-228.degree. C.
1-methyl-3-pyridinyl)methanone
oxime
(Isolated as the monohydrochloride)
17 1-[1-Cyclopentyl-1,2,5,6-
268-270.degree. C.
tetrahydro-3-pyridinyl]ethanone
oxime
(Isolated as the monohydrochloride)
18 3-Phenyl-1-(1,2,5,6-tetrahydro-
200-210.degree. C.
1-propyl-3-pyridinyl)-1-propanone
(Dec.)
oxime
(Isolated as the monohydrochloride)
19 1-(1,2,5,6-Tetrahydro-3-
227-228.degree. C.
pyridinyl)ethanone oxime
(Dec.)
(Isolated as the hydrochloride)
20 1-(1,2,5,6-Tetrahydro-1-methyl-
177-178.degree. C.
3-pyridinyl)-4-hexyn-1-one oxime
(Isolated as the monohydrochloride)
21 1-(1,2,3,6-Tetrahydro-4-pyridinyl)-
165-166.degree. C.
ethanone oxime
______________________________________
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